Computational protein design has emerged as a powerful approach for studying the structure and function of proteins. Progress in the field has allowed complex aspects of proteins, included enzymatic activity, to begin to be examined. Design of proteins with enzymatic activity has the potential to provide a new approach to exploring the fundamental mechanisms of enzyme action, and designed enzymes also have numerous possible biotechnology applications. We will use computational methods developed in the DeGrado lab to redesign the active site of a known protein to give it novel catalytic functions. Genetic selections and high-throughput screens will be developed to allow a large number of designed sequences to be analyzed. The resulting designed proteins will be fully characterized structurally and mechanistically in order to evaluate the design process and to compare them to natural enzymes. This information can then be used to improve the designs and the methodology.